Work carried out in the laboratory has characterized a new method of producing permanent sympathectomy in the rat by the administration of the antihypertensive agent, guanethidine. Our data show that this method is superior to previously used methods of producing sympathectomy, especially in the critical parameters of completeness (including vasculature) and specificity for peripheral neurons (CNS unaffected). Our objectives now are to exploit the permanent denervation of the cardiovascular system produced by guanethidine in order to define the role of the sympathetic nervous system in several forms of hypertension, to determine the mechanism by which guanethidine destroys sympathetic neurons, and to determine the reasons for the observed resistance of other species to guanethidine sympathectomy. Experiments will be carried out to determine whether animals sympathectomized by guanethidine treatment develop mineralocorticoid (DOCA-salt) hypertension or genetic hypertension (Japanese SHR rat). The hypothesis that guanethidine destroys sympathetic neurons by inhibiting utilization of nerve growth factor probably by blocking the retrograde transport of the trophic protein will be tested by monitoring accumulation of locally applied 125I-NGF in sympathetic neuron cell bodies. Experiments designed to explain the lack of effect of guanethidine on other species will involve measurement of guanethidine accumulation in ganglia of treated animals of these species (chemical assay) and by comparing the direct effects of guanethidine on the neurons (organ culture). Attempt will be made to sympathectomize these species (rabbit, cat) by combined treatment of guanethidine and the antibody to NGF. The studies will expand our knowledge of the pharmacology of guanethidine, especially as related to its cytotoxic effect on sympathetic neuron and demonstrate its utility as a tool in the understanding of the development and pathophysiology (e.g. hypertension, arrythmia) of the sympathetic nervous system.